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Increased Insulin Sensitivity and Reduced Adiposity in Phosphatidylinositol 5-Phosphate 4-Kinase ß^–/– Mice

Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Cell Biology, Harvard Medical School,¹ Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston,² Boston Biomedical Research Institute, Watertown, Massachusetts³

Received 25 November 2003/ Returned for modification 5 January 2004/ Accepted 16 March 2004

Phosphorylated derivatives of the lipid phosphatidylinositol are known to play critical roles in insulin response. Phosphatidylinositol 5-phosphate 4-kinases convert phosphatidylinositol 5-phosphate to phosphatidylinositol 4,5-bis-phosphate. To understand the physiological role of these kinases, we generated mice that do not express phosphatidylinositol 5-phosphate 4-kinase ß. These mice are hypersensitive to insulin and have reduced body weights compared to wild-type littermates. While adult male mice lacking phosphatidylinositol 5-phosphate 4-kinase ß have significantly less body fat than wild-type littermates, female mice lacking phosphatidylinositol 5-phosphate 4-kinase ß have increased insulin sensitivity in the presence of normal adiposity. Furthermore, in vivo insulin-induced activation of the protein kinase Akt is enhanced in skeletal muscle and liver from mice lacking phosphatidylinositol 5-phosphate 4-kinase ß. These results indicate that phosphatidylinositol 5-phosphate 4-kinase ß plays a role in determining insulin sensitivity and adiposity in vivo and suggest that inhibitors of this enzyme may be useful in the treatment of type 2 diabetes.

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